Table 1.
Comparison of current models of synergy methods.
| General methods | Brief description | Strengths | Limitations |
|---|---|---|---|
| Combination index | A scientific term to quantitatively depict synergism (CI < 1), additive effect (CI = 1), and antagonism (CI > 1). | 1) One of the most practical methods experimentally. 2) The most demonstrative method for the proof of synergy effects. 3) No limitation for the number of ingredients in the tested combination. |
1) Must be able to determine dose-response of individual constituents and combination. |
| Isobole method | A graphical procedure that can either represent additive, synergistic, or antagonistic interactions, depending on the position of thc dose of combination to the “iso-effect” linear line. | 1) The oldest and well-established method. 2) One of the most practical experimentally. |
1) Must be able to determine dose-response of individual constituents and combination. 2) Generally, only applicable for two drug combination. |
| Systems biology | A computational and mathematical modeling for predicting and understanding the network of components and protein/gene targtes binding biological system. | 1) Suitable for study of synergy of multi-components, prodrugs, and novel targets. 2) Being able to investigate the mechanisms of action of a combination, and identify the key active components. |
1) Large data sets including chemical, chemogenomics, pharmacological data and the compounds' potential targets information are required. |
| Methods specific in microbiology | Brief description | Strengths | Limitations |
| Diffusion assays | Positive/negative interactions in the mixture are observed via comparing the bacteria growing inhibition zone diffused in the agar with that of individual agent. | 1) Impact on microorganism can be investigated in vitro. 2) Simply, visual, qualitative representation of synergistic (or antagonistic) effect of individual components used together. |
1) These assays are subject to many variables which may influence the results and should at the most be used as a qualitative guide only. 2) Cannot differentiate synergism from additive effect. |
| Checkerboard array | The combination of two agents is contructed on a in two dimension array, and the positive/negative interactions are determined by comparing the combinational and individual inhibitory activity which can be quantified by fractional inhibitory concentration (FIC). | 1) Clear visualization on a single plate of contribution of the individual components. 2) Can test multiple concentrations simultaneously. 3) Easy to carry out and interpret |
1) Assessment of viability is not always accurate when replying on turbidometric readings. 2) Laborious for combination of three, not feasible for combinations of four or more. 3) Rely on a linear dose-response curve for all components. 4) All plants in the combination tested required to be at equal ratios. |
| Time-kill assay | Positive/negative interactions among multi-components in the mixture are determined via comparing individual and combinational bacteri cidal activity over a series of time intervals. | 1) One of the best methods to study synergy of antimicrobial agents. 2) The bacterial cidal effect is monitored over time which is not possible with the frequently used MIC assays. |
1) The method is labor intensive and requires a number of steps where variables may be introduced. 2) Difficult in interpretation of results because relatively few antibiotic concentrations are examined. 3) Rely on the reading at one time point (usually 24 h) as the sole determinant of the interaction. |